9br7

Crystal structure of human succinyl-CoA:glutarate-CoA transferase (SUGCT) in complex with Losartan carboxylic acid

spinqualitylabelsall models 9br7, resolution 2.08Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9br7 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.08Å Ligands: A1ATL, NH4, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SUCHY_HUMAN Glutaric acidemia type 3. The disease is caused by variants affecting the gene represented in this entry. Function SUCHY_HUMAN Catalyzes the succinyl-CoA-dependent conversion of glutarate to glutaryl-CoA. Can use different dicarboxylic acids as CoA acceptors, the preferred ones are glutarate, succinate, adipate, and 3-hydroxymethylglutarate. Publication Abstract from PubMed Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or nontoxic metabolites. Here, we report a putative novel target, succinyl-CoA:glutarate-CoA transferase (SUGCT), which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA and the derived 3-hydroxyglutaric acid. SUGCT is a type III CoA transferase that uses succinyl-CoA and glutaric acid as substrates. We report the structure of SUGCT, develop enzyme- and cell-based assays, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme in a high-throughput screen of FDA-approved compounds. The cocrystal structure of SUGCT with losartan carboxylic acid revealed a novel pocket in the active site and further validated the high-throughput screening approach. These results may form the basis for the future development of new pharmacological intervention to treat GA1. Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1.,Wu R, Khamrui S, Dodatko T, Leandro J, Sabovic A, Violante S, Cross JR, Marsan E, Kumar K, DeVita RJ, Lazarus MB, Houten SM ACS Chem Biol. 2024 Jul 19;19(7):1544-1553. doi: 10.1021/acschembio.4c00204. Epub , 2024 Jun 24. PMID:38915184 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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